Dataset Information

How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology.

ABSTRACT: Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-b]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of FICZ that are produced from L-tryptophan by microbes are normally degraded rapidly by the inducible cytochrome P4501A1 (CYP1A1) enzyme. This review describes how when the metabolic clearance of FICZ is attenuated by inhibition of CYP1A1, this compound passes through the intestinal epithelium to immune cells in the lamina propria. FICZ, the level of which is thus modulated by this autoregulatory loop involving FICZ itself, the AHR and CYP1A1, plays a central role in maintaining gut homeostasis by potently up-regulating the expression of interleukin 22 (IL-22) by group 3 innate lymphoid cells (ILC3s). IL-22 stimulates various epithelial cells to produce antimicrobial peptides and mucus, thereby both strengthening the epithelial barrier against pathogenic microbes and promoting colonization by beneficial bacteria. Dietary phytochemicals stimulate this process by inhibiting CYP1A1 and causing changes in the composition of the intestinal microbiota. The activity of CYP1A1 can be increased by other microbial products, including the short-chain fatty acids, thereby accelerating clearance of FICZ. In particular, butyrate enhances both the level of the AHR and CYP1A1 activity by stimulating histone acetylation, a process involved in the daily cycle of the FICZ/AHR/CYP1A1 feedback loop. It is now of key interest to examine the potential involvement of FICZ, a major physiological activator of the AHR, in inflammatory disorders and autoimmunity.

SUBMITTER: Rannug A

PROVIDER: S-EPMC7461111 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology.

Rannug Agneta A

International journal of molecular sciences 20200808 16

Ever since the 1970s, when profound immunosuppression caused by exogenous dioxin-like compounds was first observed, the involvement of the aryl hydrocarbon receptor (AHR) in immunomodulation has been the focus of considerable research interest. Today it is established that activation of this receptor by its high-affinity endogenous ligand, 6-formylindolo[3,2-<i>b</i>]carbazole (FICZ), plays important physiological roles in maintaining epithelial barriers. In the gut lumen, the small amounts of F ...[more]

PMID: 32784381

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Project description:BACKGROUND/AIMS:Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiological functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of molecules including tryptophan (TRP) metabolites to regulate physiological processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P450 1A1 (CYP1A1). METHODS:Inhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured. RESULTS:We show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of ?-napthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation. CONCLUSION:Our studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine.

Project description:Bone marrow-derived mesenchymal stem cells (BMSCs) are commonly used seed cells, and BMSC-derived primed cartilage templates have been shown to achieve bone regeneration in bone tissue engineering. Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in various cellular processes such as osteogenesis and immune regulation. This study investigated the effects of the AhR endogenous ligand 6-formyl (3,2-b) carbazole (FICZ) on the behavior of BMSCs and cartilage templates as well as the possible underlying molecular mechanisms. AhR expressions in rat bone marrow and isolated BMSCs were detected via immunohistochemistry (IHC) and immunofluorescent staining. Alkaline phosphatase staining and alizarin red staining showed that FICZ treatment enhanced the osteogenic potential of BMSCs without influencing their proliferation. FICZ was shown to alleviate the LPS-induced inflammatory cytokines IL-1β, 6 and TNF-α via the quantitative polymerase chain reaction (qPCR). In the chondrogenic process from BMSCs to primed cartilage templates, the expressions of AhR and its target gene cytochrome P450 subfamily B member 1 (CYP1B1) were inhibited. However, IHC staining demonstrated that AhR was still involved in the subcutaneous ossification of cartilage templates. Then, the effects of FICZ on cartilage templates were investigated. The osteogenic markers were upregulated by FICZ administration. The RAW 264.7 treated by condition medium of FICZ-treated cartilage templates exhibited an anti-inflammatory phenotype. Finally, high-throughput sequencing was applied to analyze the differentially expressed genes (DEGs) in the FICZ-treated cartilage templates. The upregulation of cytochrome P450 subfamily A member 1 (CYP1A1) and sphingomyelin phosphodiesterase 3 (Smpd3) were verified by qPCR, which might be the downstream targets of AhR in the cartilage templates promoting osteogenesis and macrophage polarization. These data implied a beneficial role of FICZ in the regenerative potentials of both BMSCs and primed cartilage templates. The FICZ/AhR axis might be a practical target to achieve optimal bone regeneration.

Dataset Information

How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology.

Publications

How the AHR Became Important in Intestinal Homeostasis-A Diurnal FICZ/AHR/CYP1A1 Feedback Controls Both Immunity and Immunopathology.

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